Targeting parvalbumin neurons in the PFC for cognitive deficits Abstract: Treatment-resistant cognitive deficits in schizophrenia (SZ) represent a significant clinical burden and are the primary predictor of functional outcome in individual patients. Although the mechanisms associated with cognitive deficits remain unclear, pathological GABAergic signaling likely plays an essential role. Deficits in parvalbumin (PV)-containing fast-spiking (FS) interneurons in the prefrontal cortex (PFC) are consistently found in post-mortem tissue of patients with SZ. In addition, the observation of decreased PV cells has been replicated across a wealth of SZ animal models, suggesting this pathology may represent a convergence point in this disorder. Specifically, our studies have shown a significant decrease of synaptic inhibition and PV interneurons in the PFC, along with working memory and learning deficits in both rat methylazoxymethanol acetate (MAM) exposure and NMDA receptor antagonist MK-801 models for SZ, analogous to endophenotypes seen in clinical populations. These findings not only highlight the importance of PV neurons in the pathological processes of SZ, but also a potential causal link between the impaired PV cells and cognitive deficits. However, it remains unclear whether directly targeting PV neurons in the PFC is capable of ameliorating cognitive deficits. We hypothesize that decreased inhibitory neurotransmission in the PFC underlies cognitive deficits in these two animal models of SZ, whereas augmenting the activity of the remaining PV interneurons will alleviate the cognitive impairments by adjusting excitation/inhibition balance in the PFC circuitry. Thus, the goal of this study is to improve cognitive performance by utilizing a targeted pharmacogenetic upregulation of PV interneuron activity, with a novel excitatory DREADD. This will follow electrophysiological tests to elucidate the mechanisms through which the DREADD affects prefrontal cortical function in both neurodevelopmental and pharmacological models for SZ. This study will have translational implications for clarifying how disrupted inhibitory circuitry plays a role in cognitive deficits in SZ and will help to answer a fundamental question of whether cognitive impairment can be improved by enhancing the neuronal activity of a specific subtype of GABAergic interneurons in the PFC. Further, it will provide important insight into treating other disorders with cognitive symptoms.